The polysaccharide, or O-antigen (O-Ag), portion of lipopolysaccharide (LPS) of Salmonellae plays a crucial role in the killing of these bacteria by the host humoral system. Specifically, the O-Ag structure directly effects the rate and extent of deposition of the complement component C3b on the cell surface by affecting the initial amount of C3b deposited and by influencing the subsequent interaction of this C3b with factor b. O-Ag structure does not influence the inactivation of bound C3b. Similarly, the O-Ag size and density on the surface of Salmonellae montevideo cells is responsible for the extent of killing of the cells by normal human serum. Survival in serum was associated with LPS that contained O-Ag side chains of at least 4-5 subunits in length and with about 20% of the LPS cores being substituted with O-Ag side chains of length more than 14 subunits. It is proposed that the O-Ag functions to provide serum resistance by sterically hindering access of the C5b-9 complex to the cell membrane. E. coli cells grown in the presence of 5 mM sodium salicylate become phenotypically resistant to a variety of antibiotics. This resistance begins within 5 minutes after the addition of salicylate and does not involve marked alterations in the pattern of protein or LPS isolated from the outer membrane. We have developed an assay to show that the salicylate-induced drug resistance is due to a 75-80% decrease in the permeability of the outer membrane.